Pancreatic cancer is a highly lethal disease that is very difficult to diagnose. The high mortality of this disease is predominantly due to the advanced stage of disease at the time of diagnosis and a lack of effective treatments. Due to the low prevalence of pancreatic cancer (0.01%), early detection would be most cost-effective in screening increased-risk populations, such as new-onset type-2 diabetics. Clinical and research studies have substantiated the link between pancreatic cancer and new-onset type-2 diabetes. Development of a highly accurate blood-based test to detect pancreatic cancer in this population would represent a breakthrough in early detection of pancreatic cancer. Such a blood test, if used on an annual basis in this higher-risk population, could serve as an effective and inexpensive method for initial targeted screening. In this project, we proposed to develop and characterize a blood-based proteomics signature that allows early detection of pancreatic cancer patients with new-onset diabetics. The Specific Aims are as follows: Specific Aim 1: unbiased global discovery of differential proteins associated with pancreatic cancer in the blood of diabetic patients using quantitative proteomics; Specific Aim 2: development of targeted proteomics assay for 35 selected biomarker candidates; Specific Aim 3: establishment of a proteomics signature (biomarker panel) for detecting early stage pancreatic cancer in diabetic patients; Specific Aim 4: evaluation of the proteomics signature in detecting pancreatic cancer in asymptomatic patients. This proposal builds on our decade-long systematic study of pancreatic tumorigenesis, the rich resource of previous discoveries in pancreatic cancer biomarker development, well-characterized study cohorts from different institutions, as well as cutting-edge proteomics platform technologies that we have developed and implemented. Successful development of a blood-based assay to facilitate the early detection of pancreatic cancer for diabetic patients would alleviate the current prolonged work-up of higher-risk populations and provide critically important interception opportunities to treat earlier stage cancer.